BACE Inhibitors

Wyss, Daniel F.; Cumming, Jared N.; Strickland, Corey; Stamford, Andrew W.

doi:10.1002/9783527683604.ch14

Cited by 3 publications

(1 citation statement)

References 65 publications

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“…As shown in Figure , our work in this area began with the identification of isothiourea 1 through a fragment-based approach, and we have disclosed the progression of this fragment via lead compound 2 to high affinity brain penetrant and bioavailable inhibitors belonging to two distinct chemical series, iminohydantoins (e.g., 3 ) and iminopyrimidinones (e.g., 4 and 5 ) . These efforts, independent of others achieved through HTS and fragment-based approaches, involved significant de novo design elements with extensive application of X-ray crystallography and molecular modeling. In the iminopyrimidinone series, additional SAR development that focused on structural diversity and conformational constraint led to design of a novel bicyclic iminopyrimidinone scaffold represented by compounds 6 , 7 and 8 (Figure ).…”

Section: Introductionmentioning

confidence: 99%

Structure-Based Design of an Iminoheterocyclic β-Site Amyloid Precursor Protein Cleaving Enzyme (BACE) Inhibitor that Lowers Central Aβ in Nonhuman Primates

Mandal

Misiaszek

et al. 2016

J. Med. Chem.

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We describe successful efforts to optimize the in vivo profile and address off-target liabilities of a series of BACE1 inhibitors represented by 6 that embodies the recently validated fused pyrrolidine iminopyrimidinone scaffold. Employing structure-based design, truncation of the cyanophenyl group of 6 that binds in the S3 pocket of BACE1 followed by modification of the thienyl group in S1 was pursued. Optimization of the pyrimidine substituent that binds in the S2'-S2″ pocket of BACE1 remediated time-dependent CYP3A4 inhibition of earlier analogues in this series and imparted high BACE1 affinity. These efforts resulted in the discovery of difluorophenyl analogue 9 (MBi-4), which robustly lowered CSF and cortex Aβ40 in both rats and cynomolgus monkeys following a single oral dose. Compound 9 represents a unique molecular shape among BACE inhibitors reported to potently lower central Aβ in nonrodent preclinical species.

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Section: Introductionmentioning

confidence: 99%

Structure-Based Design of an Iminoheterocyclic β-Site Amyloid Precursor Protein Cleaving Enzyme (BACE) Inhibitor that Lowers Central Aβ in Nonhuman Primates

Mandal

Misiaszek

et al. 2016

J. Med. Chem.

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NMR Studies of Protein–Small Molecule Interactions for Drug Discovery

Wyss

Zartler

2020

Structural Biology in Drug Discovery

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Spiropiperidine Sultam and Lactam Templates: Diastereoselective Overman Rearrangement and Metathesis followed by NH Arylation

et al. 2017

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We report the diastereoselective synthesis of novel spiropiperidine templates for use in SAR studies of β-secretase (BACE) inhibitors and also as versatile ligands for other receptor types. The overall synthetic approach stems from chiral starting material benzyl (S)-2-methyl-4-oxopiperidine-1-carboxylate and employs an Overman rearrangement to control the stereochemistry at the quaternary center. This process is followed by a Grubbs metathesis to close a five-membered "top" ring to form an α,β-unsaturated lactam or an α,β-unsaturated sultam. We also demonstrate that this chemistry can accommodate additional substituents on the lactam/sultam ring and allows late stage sequential functionalization of the amine and amide nitrogens to rapidly produce diverse analogues.

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BACE Inhibitors

Cited by 3 publications

References 65 publications

Structure-Based Design of an Iminoheterocyclic β-Site Amyloid Precursor Protein Cleaving Enzyme (BACE) Inhibitor that Lowers Central Aβ in Nonhuman Primates

Structure-Based Design of an Iminoheterocyclic β-Site Amyloid Precursor Protein Cleaving Enzyme (BACE) Inhibitor that Lowers Central Aβ in Nonhuman Primates

NMR Studies of Protein–Small Molecule Interactions for Drug Discovery

Spiropiperidine Sultam and Lactam Templates: Diastereoselective Overman Rearrangement and Metathesis followed by NH Arylation

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